Omeprazole, the generic name for 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benz imidazole (denoted as Formula I below) is a well-described gastric proton-pump inhibitor and is on the market as LOSEC.RTM. or PRILOSEC.RTM. for the treatment of gastric and duodenal ulcers, gastritis, duodenitis, and reflux esophagitis (see Merck Index, 12th Ed., entry 6977, and references cited therein). Omeprazole is commercially prepared via a multi-step sequence, the last step of which is oxidation of the sulfide intermediate, 5-methoxy-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]thiol]-1H-benzimida zole (denoted as Formula II below), known generically as pyrmetazole, which is typically effected with a peroxy acid, such as meta-chloroperoxybenzoic acid (hereinafter referred to as MCPBA) (U.S. Pat. Nos. 4,255,431; 5,386,032; and EPO 484,265), magnesium monoperoxyphthalate (MMPP) (U.S. Pat. No. 5,391,752), or peroxyacetic acid (WO 98/09962), in a suitable non-alcoholic organic reaction solvent. ##STR1##
Oxidants other than peroxyacids have also been used for the oxidation of pyrmetazole to omeprazole. EPO 302,720 utilizes aqueous hydrogen peroxide in the presence of a vanadium catalyst, Spanish application No. ES 550,070 discloses periodate as the oxidant, and Spanish applications No. ES 539,793 and ES 540,147 describe iodosobenzene and 3-methyliodosobenzene, respectively. A photooxidative method is disclosed in GB 2,239,453.
Reduction of omeprazole-N-oxide to omeprazole is described in WO 98/40377 and WO 98/40378.
The preferred oxidizing agent is usually MCPBA, and suitable non-alcoholic organic reaction solvents include aromatic hydrocarbon solvents, such as benzene and toluene or a mixture thereof, and chlorinated aliphatic hydrocarbon solvents, such as chloroform, 1,2-dichloroethane, and methylene chloride or a mixture thereof, in admixture with an alcoholic solvent, such as methanol, ethanol, isopropanol, or 1-butanol. The preferred non-alcoholic organic reaction solvent is usually chloroform, methylene chloride, or toluene, and the preferred alcoholic solvent is ethanol.
Prior processes to omeprazole have numerous disadvantages that limit both the yield and the purity of the final product.
A significant drawback of such prior methods is incomplete oxidative conversion of pyrmetazole into omeprazole as well as over-oxidation. Two such by-products of over-oxidation are the sulfone of structural formula V and the sulfone-N-oxide of structural formula VI. Incomplete and over-oxidation, characteristic of the previous methods, arise from ineffective control over the amount of the oxidizing agent as well as the manner in which the oxidizing agent is charged into the reaction vessel. Prior methods do not use accurately determined amounts of the oxidizing agent and do not provide for careful control of its addition to the reaction mixture. Incomplete and over-oxidation both contribute to the presence of impurities and loss of yield of the final desired product. ##STR2##